Summary of Work: One out of every eight women in the United States will be affected by breast cancer in her lifetime. Breast cancer is a multi- faceted disease that is influenced by many factors including genetics, as well as endo- genous and exogenous environmental factors. We are interested in determining the environmental agents that influence the course of this disease and how these environmental factors interplay with products of breast cancer susceptibility genes. Currently we are developing a check- point model, using normal breast epithelial cells, that will be used to screen for a variety of agents, including non- genotoxic carcinogens, that may cause progression, or loss of checkpoint function in this cell type. In addition, we are specifically investigating the function of the breast and ovarian susceptibility gene, BRCA1. We have found that decreased expression of BRCA1 using antisense cDNA results in an increase in tumorigenicity and anchorage- independence, as well as a growth advantage in normal growth restrictive conditions, such as low estrogen. Investigation of the expression of BRCA1 protein revealed the distinct expression of an alternately spliced form of the BRCA1 protein. Currently studies are underway to determine the role of BRCA1 in the cellular response to irradiation and oxidative damage, as well as the effect of carcinogen treatment on BRCA1 levels/function. Finally, the role of the IGFI and the progression of breast carcinoma is being investigated. We have shown that decreased expression of IGFI by dietary restriction can reduce the formation of advanced bladder carcinomas in mice. We have now extended this observation to breast tumor development and have shown that decreased activation of the IGF pathway by treatment of cells with the soluble IGFIR results in a significant decrease of invasion potential and metastases of the breast cell line, MDAMB435.